ORIGINAL ARTICLE

Hostile Marital Interactions, Proinflammatory

Cytokine Production, and Wound Healing
Janice K. Kiecolt-Glaser, PhD; Timothy J. Loving, PhD; Jeffrey R. Stowell, PhD; William B. Malarkey, MD;
Stanley Lemeshow, PhD; Stephanie L. Dickinson, MAS; Ronald Glaser, PhD

Context: A growing epidemiological literature has sug-
gested that marital discord is a risk factor for morbidity
and mortality. In addition, depression and stress are as-
sociated with enhanced production of proinflammatory
cytokines that influence a spectrum of conditions asso-
ciated with aging.
Objective: To assess how hostile marital behaviors
modulate wound healing, as well as local and systemic
proinflammatory cytokine production.
Design and Setting: Couples were admitted twice to
a hospital research unit for 24 hours in a crossover trial.
Wound healing was assessed daily following research unit
discharge.
havior, wound healing, and local and systemic changes
in proinflammatory cytokine production were assessed
during each research unit admission.
Results: Couples’ blister wounds healed more slowly and
local cytokine production (IL-6, tumor necrosis factor
␣, and IL-1␤) was lower at wound sites following mari-
tal conflicts than after social support interactions. Couples
who demonstrated consistently higher levels of hostile
behaviors across both their interactions healed at 60%
of the rate of low-hostile couples. High-hostile couples
also produced relatively larger increases in plasma IL-6
and tumor necrosis factor ␣ values the morning after a
conflict than after a social support interaction com-
pared with low-hostile couples.

Participants: Volunteer sample of 42 healthy married
couples, aged 22 to 77 years (mean [SD], 37.04 [13.05]),
married a mean (SD) of 12.55 (11.01) years.
Interventions: During the first research unit admis-
sion, couples had a structured social support interac-
tion, and during the second admission, they discussed a
marital disagreement.
Conclusions: These data provide further mechanistic evi-
dence of the sensitivity of wound healing to everyday
stressors. Moreover, more frequent and amplified in-
creases in proinflammatory cytokine levels could accel-
erate a range of age-related diseases. Thus, these data also
provide a window on the pathways through which hos-
tile or abrasive relationships affect physiological func-
tioning and health.

Main Outcome Measures: Couples’ interpersonal be- Arch Gen Psychiatry. 2005;62:1377-1384

Author Affiliations:
Departments of Psychiatry
(Dr Kiecolt-Glaser) and Internal
Medicine (Drs Malarkey and
Glaser), Institute for Behavioral
Medicine Research
(Drs Kiecolt-Glaser, Malarkey,
Lemeshow, and Glaser),
Comprehensive Cancer Center
(Drs Malarkey and Glaser),
School of Public Health
(Dr Lemeshow), and Center for
Biostatistics (Dr Lemeshow and
Ms Dickinson), Ohio State
University, Columbus;
Department of Human Ecology,
University of Texas, Austin
(Dr Loving); Department of
Psychology, Eastern Illinois
University, Charleston
(Dr Stowell).
M
ARRIAGE IS THE CEN -
tral relationship for the
majority of adults, and
morbidity and mortal-
ity are reliably lower
for married individuals than unmarried in-
dividuals across such diverse health threats
as cancer, heart attacks, and surgery.1-4 Al-
though loss of a spouse through death or
divorce can provoke adverse mental and
physical health changes,1,5-7 the simple
presence of a spouse is not necessarily pro-
tective; a troubled marriage is itself a prime
source of stress, while simultaneously lim-
iting the partner’s ability to seek support
in other relationships.8 The impact of a tur-
bulent marriage is substantial; for ex-
ample, epidemiological data demon-
strated that unhappy marriages were a
potent risk factor for major depressive dis-
order, associated with a 25-fold increase
relative to untroubled marriages.9 Simi-
larly, other researchers found a 10-fold in-
crease in risk for depressive symptoms as-
sociated with marital discord.10
Marital discord also has substantial
physiological repercussions. For ex-
ample, in a population-based, prospec-
tive study of women aged 30 to 65 years
with coronary heart disease, marital stress
worsened the prognosis 2.9-fold for re-
current coronary events.11 Among pa-
tients with congestive heart failure, mari-
tal quality predicted 4-year survival as well
as the patient’s illness severity.12 Greater
marital conflict was associated with a 46%
higher relative death risk among female pa-
tients undergoing hemodialysis.13
Laboratory studies have provided evi-
dence of possible mechanisms. For ex-
ample, discussion of a marital disagree-
ment produced clinically significant

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increases in blood pressure in patients with hyperten-
sion, with subjects reaching a mean of 160/100 mm Hg.
These blood pressure changes were specifically associ-
ated with hostile marital interactions; neither support-
ive nor neutral behaviors were significantly associated
with blood pressure changes.14 Similarly, newlywed
couples who exhibited more hostile behaviors during a
marital problem discussion showed greater decrements
over 24 hours on a battery of functional immunological
assays relative to low-hostile couples.15 Endocrine data
from these same newlyweds also demonstrated the im-
pact of hostile behaviors; more hostile couples showed
more persistent elevations in serum epinephrine, nor-
epinephrine, and corticotropin levels during the con-
flict discussion,16 as well as greater elevations in stress
hormone levels throughout the remainder of the day.17
Indeed, hostile marital conflicts can have adverse physi-
ological effects even in long-term marriages; endocrine
and immunological data were associated with hostile con-
flict behavior in older couples who had been married an
average of 42 years.18
Thus, a series of studies have shown that marital con-
flict alters physiological functioning, and hostile behav-
ior, particularly during conflict, markedly enhances ad-
verse physiological changes; moreover, women appear
to be more adversely affected than men.5 In this study,
we extended this line of research to assess how hostile
marital behavior modulated an important health out-
come, wound healing, as well as local and systemic pro-
inflammatory cytokine production.
Several studies have revealed large and reliable rela-
tionships between stress and wound healing.19,20 Stress
slows the local production of proinflammatory cyto-
kines at wound sites, providing evidence of 1 key mecha-
nism21; cytokines play important roles in the early stage
of wound healing, acting as chemoattractants for the mi-
gration of phagocytes and other cells to wound sites, start-
ing the proliferative phase, which involves the recruit-
ment and replication of cells necessary for tissue
regeneration and capillary regrowth.22 Thus, stress-
related delays are important because early events in wound
healing, particularly in the first 24 hours, represent a criti-
cal period, and dysregulation during this interval poten-
tiates later problems.23
Although greater early local production of proinflam-
matory cytokines at wound sites is beneficial because it
is associated with enhanced healing, greater systemic pro-
duction of proinflammatory cytokines can represent a mal-
adaptive response.24 Both physical and psychological
stressors can provoke transient increases in plasma lev-
els of proinflammatory cytokines, particularly IL-6,25 as
can negative emotions like depression and anxiety.26-28
More frequent or persistent stress-related changes have
broad implications for physical and mental health; sus-
tained elevated levels of proinflammatory cytokines have
been linked to a variety of age-related diseases, includ-
ing cardiovascular disease, osteoporosis, arthritis, type
2 diabetes mellitus, certain cancers, and frailty and func-
tional decline.29-31
To separate the effects of the short-term stress of a mari-
tal conflict from the long-term strains of marital discord
on local and systemic proinflammatory cytokine pro-
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duction as well as wound healing, couples were re-
cruited for two 24-hour admissions to our General Clini-
cal Research Center (GCRC). On each admission, a
suction blister protocol provided a mechanism for study-
ing the local inflammatory responses in vivo22; healing
at the blister sites was assessed daily following GCRC dis-
charge. During the first GCRC admission, spouses had
a structured social support interaction; during the sec-
ond admission, couples discussed an area of disagree-
ment. Thus, the present study assessed production of pro-
inflammatory cytokines in peripheral blood and wound
sites following socially supportive and conflictual inter-
actions.
We expected that higher levels of hostile marital be-
havior would be associated with slower healing of wounds,
lower production of proinflammatory cytokines in blis-
ter chamber fluid, and higher cytokine production in pe-
ripheral blood; however, short-term marital strife would
magnify these relationships such that more hostile couples
would show relatively greater deficits on these dimen-
sions relative to low-hostile couples during and follow-
ing the conflict visit. Women were expected to show
greater psychological and physiological responsiveness
to conflict than men.
METHODS
PARTICIPANTS
Couples were recruited through newspaper and radio ads, no-
tices posted on campus and in the community, and referrals
from other participants. Exclusion criteria included health prob-
lems (or related medications) that had an immunological or
endocrinological component or obvious consequences for these
systems or for wound healing (eg, cancer, recent surgeries,
strokes, diabetes mellitus, peripheral vascular disease, condi-
tions such as asthma or arthritis that required regular use of
antiinflammatories, etc). We excluded couples if either spouse
took blood pressure medication, smoked, or used excessive al-
cohol or caffeine; 224 couples were excluded because at least
one spouse did not meet our stringent health criteria. The Ohio
State University Biomedical Research Review Committee (Co-
lumbus) approved the project; all subjects gave written in-
formed consent prior to participation.
OVERVIEW, GCRC ADMISSIONS
The procedures and timetable were similar across couples’ two
24-hour admissions to the GCRC, a hospital research unit. We
asked couples not to drink or eat anything after midnight be-
fore admission; all couples were served the same meals in the
GCRC, controlling for dietary factors such as sodium. To as-
sure consistent physical activity across dyads and admissions,
couples remained together in the same room.
At 7 AM, couples were admitted to the GCRC, fed a standard
breakfast, and given questionnaires to complete. A heparin well
was inserted in each subject’s arm, and a baseline blood sample
was drawn for immunological assays. At 9:15 AM, nurses at-
tached the vacuum pump and template to raise blisters on the
arm21 (see “Suction Blister Studies” subsection of the “Methods”
section). At roughly 10:45 AM, couples were positioned in chairs
facing each other in front of a curtain. The couples completed
several questionnaires, then sat quietly for 10 minutes.
During the first GCRC admission, two 10-minute discus-
sions assessed couples’ behavior toward each other when so-
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liciting and offering social support.32 The first spouse, selected
randomly, was asked to “talk about something you would like
to change about yourself,” while the partner was instructed to
“be involved in the discussion and respond in whatever way
you wish.” Roles were reversed after 10 minutes so that each
spouse played the role of helper or helpee. Prior to the discus-
sions, each spouse was asked to identify an important per-
sonal characteristic, problem, or issue that he or she wished to
change, with the explicit restriction that the issue could not
be a source of marital dissension.32 Next, using the Relation-
ship History Interview,33 couples were asked to tell the story
of their relationship for 30 minutes.
The second GCRC admission included the conflict resolu-
tion task; the experimenter first conducted a 10- to 20-minute
interview to identify the best topics for the problem discus-
sion.15 Based on their ratings from the Relationship Problem
Inventory34 and this interview, couples were then asked to dis-
cuss and try to resolve 1 or 2 marital issues that the inter-
viewer judged to be the most conflict producing (eg, money,
communication, or in-laws). The research team remained out
of sight during all discussions.
Fluid was removed from blister chambers 4, 7, and 22 hours
after raising the blisters. After removal of the blister chamber
at 7 AM, participants completed final questionnaires and pro-
vided peripheral blood samples for cytokine assays.
OBSERVATIONAL CODING SYSTEM
The Rapid Marital Interaction Coding System (RMICS)35 pro-
vided data on behavior during both the social support and con-
flict resolution tasks. The RMICS includes 11 communication
categories coded in a hierarchy. The RMICS discriminates well
between distressed and nondistressed couples. The RMICS has
high reliabilities both for the overall system as well as for in-
dividual codes.35 Our tapes were coded by Richard Heyman,
PhD, University of New York at Stony Brook.
Most marital communication studies use a positive/negative
distinction when assembling summary codes14,36 because dis-
tressed marriages are characterized by negative affect, conflict-
ual communication, and poor listening skills.37-40 To capture these
dimensions in composite indexes, we summed the top 3 RMICS
codes in the hierarchy: psychological abuse (eg, disgust, con-
tempt, belligerence, as well as nonverbal behaviors like glower-
ing or talking in a threatening or menacing manner), distress-
maintaining attributions (eg, “You’re only being nice so I’ll have
sex with you tonight” or “You were being mean on purpose”),
and hostility (eg, criticism, hostile voice tone, or rolling the eyes
dramatically). The remaining codes (in order) are dysphoric affect,
withdrawal, acceptance, relationship-enhancing attributions, self-
disclosure, humor, constructive problem discussion, and “other.”
QUESTIONNAIRES
We also assessed emotional responses to the marital discus-
sions, as well as perceptions of marital satisfaction. Couples
completed the two 10-item mood scales from the Positive and
Negative Affect Schedule (PANAS)41 before and after their dis-
cussions. The widely used Marital Adjustment Test provided
data on marital satisfaction, with higher scores indicating
greater satisfaction.42
Health-related behaviors assessed at screening and/or GCRC
admission included medications, exercise, and caffeine and al-
cohol intake.43,44 The Pittsburgh Sleep Quality Index45 as-
sessed sleep quality and disturbances. Plasma albumin levels
and body mass data provided information on subjects’ nutri-
tional status. Health questions from the Older Adults Re-
sources Survey46 assessed underlying diseases.
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PLASMA AND CHAMBER-FLUID
CYTOKINE LEVELS
Plasma IL-6 and tumor necrosis factor ␣ (TNF-␣) levels and
chamber-fluid IL-6, TNF-␣, and IL-1␤ levels were assayed us-
ing Quantikine High Sensitivity Immunoassay kits (R&D Sys-
tems, Minneapolis, Minn), per kit instructions, as described else-
where.47 Samples were run undiluted in duplicate, and all
samples for a couple were run at the same time.
SUCTION BLISTER STUDIES
The suction blister protocol followed the methods described
previously21,22,48,49 and used the same suction blister device
(Neuro Probe, Cabin John, Md).49 To assess the early phase of
the inflammatory response to wounding in vivo, a plastic tem-
plate was taped to the volar surface of the nondominant fore-
arm (shifted slightly laterally for the second GCRC admis-
sion); a 350–mm Hg vacuum was applied through a pump
attached to a regulator until blisters formed (1-1.5 hours). This
gentle suction produced 8 small 8-mm blisters. The blister roof
(the epidermis) was removed with sterile scissors, a plastic tem-
plate with 8 wells was placed over the blister wounds and taped
to the arm, the wells were filled with 0.8 to 1 mL of 70% au-
tologous serum in Hank balanced salt solution,49 and the top
was sealed. Chamber fluid from 3 wells was pooled for the 4-
and 7-hour samples, and 2 wells were pooled for the 22-hour
sample. The pooled samples were analyzed for cytokine levels
and cell numbers.21,22 These procedures produce modest self-
rated discomfort, consistent with the small and transient car-
diovascular changes observed during blistering.21
Suction blister wounds are an excellent model for studying
the effects of early wound healing.50 Measurement of the rate
of transepidermal water loss (TEWL) through human skin pro-
vides a noninvasive method to monitor changes in the stra-
tum corneum barrier function of the skin, providing an excel-
lent objective method for evaluation of wound healing.51 The
8 blister sites were assessed daily for 8 days following removal
of the blister chambers50 and then again on day 12, along with
daily control values from adjacent nonwounded skin; after sub-
tracting the average control values from the average daily mea-
surement, the 90% standard for healing was based on reach-
ing 90% of the day 1 measures. A computerized evaporimetry
instrument, the DermaLab (CyberDERM, Media, Pa), was used
to measure TEWL, following established procedural guide-
lines.52
DATA ANALYSES
High- and Low-Hostile Groups
Husbands’ and wives’ hostile behaviors on the RMICS were sig-
nificantly correlated ([Spearman ␳], r=0.66 during social sup-
port and r=0.79 during conflict; P⬍.001 for both). Thus, follow-
ing methods in other marital research, we summed the hostile
behavior percentages within each GCRC admission for each
couple.14,53 Also, we were interested in the couple’s aggregate hos-
tile behavior because one partner’s behavior clearly affects the other.
Behavioral data were skewed at both GCRC admissions; dur-
ing the social support interactions, 2 or fewer of the total dy-
adic behaviors were categorized as hostile in 56.1% of couples
(range, 0-27). Indeed, even during conflict discussions, 50%
of couples had 7 or fewer hostile behaviors (range, 0-63). Ac-
cordingly, because our interest was in the effects of recurring
or customary hostility, we categorized couples who were higher
than the median on hostile behaviors at both GCRC admis-
sions as high hostile (28.6% of the sample) and the remainder
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as low hostile; thus, a couple was not classified as hostile sim-
ply because they had 1 bad day.
Wound Healing
Using survival analysis54 to investigate wound healing, the
“event” was defined as the first point that the wound was 90%
healed using TEWL data and remained higher than 90%. Par-
ticipants with a ratio less than 90% at their last observed point,
either by day 12 or earlier, were censored at that point.
The Cox proportional hazards model with clustering on
couple55 in Stata 8.0 (Stata Corp, College Station, Tex) com-
pared time to healing between the high- and low-hostile be-
havior groups at each visit, controlling for sex. Subjects’ times
to healing were also compared between the 2 visits in a third
model. The assumption of proportional hazards across groups
was tested after fitting each model. Missing data occurred at
varying points because of technical difficulties and missed ap-
pointments. Where necessary, time to healing was calculated
using last observation carried forward.
Immunological and Psychological Data
To analyze relationships among behavior (high vs low hos-
tile) on the cytokine levels of each subject at each visit (social
support or conflict) and each point, mixed models from SAS
9.1 (SAS Institute Inc, Cary, NC) were used with repeated mea-
sures across spouse, visit, and time of day. An unstructured co-
variance matrix was used to allow for the most flexible esti-
mation of covariance parameters between each level of spouse,
visit, and time. The mixed models also allowed use of partial
data when subjects had occasional missing data.
Prior to analyses, cytokine data were normalized with log
transformations. Log transformations did not normalize the data
for PANAS negative mood and cell numbers; thus, the ranks
of the data were used in a linear mixed model of PANAS nega-
tive mood, and cell number data were analyzed using area un-
der the curve across the 3 points. All tests used a 2-sided, ␣=.05
significance level.
RESULTS
The 42 couples ranged in age from 22 to 77 years (mean
[SD], 37.04 [13.05]) and had been married a mean (SD)
of 12.55 (11.01) years (range, 2-52 years). Couples were
well educated: 26.2% had additional postgraduate train-
ing, 40.5% were college graduates, 23.8% had some col-
lege training, and 9.5% were high school graduates. The
majority were white (88.1%). A mean (SD) of 2.37 (1.93)
months elapsed between the 2 GCRC admissions. Four
additional couples did not return for the second admis-
sion because of scheduling or medical problems (eg, a
cancer diagnosis) and thus could not be included in these
analyses.
The high- and low-hostile behavior groups did not dif-
fer on age or education (F ⬍1; P⬎.44 for both). The 2
groups did not differ on the duration of their marriages
or the length of time between GCRC admissions (F ⬍1.57;
P⬎.21 for both).
Analysis of RMICS positive behaviors (the sum of ac-
ceptance, relationship-enhancing attributions, self-
disclosure, humor, and constructive problem discus-
sion) indicated theoretically consistent significant
differences between high- and low-hostile groups; the
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sex ⫻group interaction reflected women’s larger differ-
ences than men’s (F1,40 =5.84; P=.02). That is, while high-
hostile men showed only slightly fewer positive behav-
iors than low-hostile men (mean difference, 3.19), the
difference between low- and high-hostile women was
much larger (mean, 8.08). Not surprisingly, there were
fewer positive behaviors in the conflict visit than in the
social support visit (F1,40 =15.02; P⬍.001).
In accord with RMICS behavioral data, high-hostile par-
ticipants reported lower marital satisfaction than low-hostile
participants on the Marital Adjustment Test42 (F1,39 =4.42;
P=.04), with no significant sex differences. The low-hostile
group mean (SD) score was 120.13 (18.11), compared with
107.95 (21.60) for high-hostile participants.
High- and low-hostile behavior groups did not differ
at baseline at either GCRC admission on either the Posi-
tive or Negative Affect scales from the PANAS56 (F ⬍1;
P⬎.46 for both). The absence of any baseline affective
group differences is important because affective differ-
ences are related to plasma proinflammatory cytokine pro-
duction,27,57 as well as wound healing.19,20 Negative mood
ratings at the first GCRC admission started off higher than
in the second GCRC admission and decreased after the
interaction, while ratings at the GCRC conflict admis-
sion increased (F1,40 =12.12; P=.01). However, high- and
low-hostile behavior subjects had a different pattern of
response to the spousal interactions as reflected in their
PANAS negative mood ratings, after controlling for visit;
high-hostile subjects’ moods were more negative after each
of the interactions, while low-hostile subjects’ moods were
less negative (F1,40 =5.24; P=.03).
WOUND HEALING
High-hostile subjects had a median time to healing 1 day
later than low-hostile subjects at the social support visit
(day 6 vs day 5, respectively) and at the conflict visit (day
7 vs day 6, respectively). Ignoring visit, median time to
healing was 2 days later in the high-hostile behavior group
(day 7 vs day 5). Ignoring hostile behavior, time to heal-
ing was 1 day later following the conflict visit than after
the social support visit (day 6 vs day 5).
Comparisons of the Kaplan-Meier survival curves be-
tween hostile behavior groups using the log-rank test
yielded P=.02 at the social support visit, P=.07 for the
conflict visit, and P = .004 for the combined visits
(Figure 1A). Figure 1B displays a comparison of Kaplan-
Meier survival curves for time to healing after each visit
(P=.046); however, the log-rank tests are limited in com-
parison to Cox models because they cannot adjust for co-
variates in the model or for clustering within couple.
Using Cox models, the hazard ratio (HR) for the hos-
tile behavior groups at the social support visit, control-
ling for sex, was 0.592 (P = .04). This means the esti-
mated “risk” of 90% TEWL healing on any given day for
the high-hostile subjects was 0.592 times that of low-
hostile participants. At the conflict visit, the HR for the
hostile groups was 0.618 (P=.08). Combining visits, high-
hostile group subjects healed slower than those in the
low-hostile group (HR, 0.598; P=.03), controlling for sex
and visit. In the model across both visits, healing was sig-
nificantly slower after the conflict visit (HR, 0.726; P=.01),
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 A
A 9.75
1.00 Social Support Visit
Low-Hostile Behavior Conflict Visit
High-Hostile Behavior
8.75

IL-6 (log10), pg/mL

0.75
Survival Function

7.75
1
0.50

6.75
1
0.25 7

7 5.75

0
4 7 22
0 5 10 15
B
7
B
1.00
Social Support, Visit 1 6
Conflict, Visit 2

TNF-α (log10), pg/mL

5
0.75
1
Survival Function

4
0.50
3

0.25 1 2
77
1
0 4 7 22
0 5 10 15
C
Days After Wounding 7

Figure 1. Kaplan-Meier survival curves for time to healing of the standard 6

wound across both visits by high- or low-hostile behavior (A) and for time to
IL-1β (log10), pg/mL

healing of the standard wound by visit (B). Couples who demonstrated

5
consistently higher levels of hostile behaviors across both their interactions
healed at 60% of the rate of low-hostile couples, and healing during the
conflict visit was at 72% of the rate observed following the social support 4
visit. Annotations on the curves show the number of censored observations
at each point, indicating patients who were unhealed on their last day of 3
observation.
2

controlling for sex and hostile behavior group. Al- 1

though not statistically significant, men healed slightly 4 7 22
slower than women at the social support visit (HR, 0.975) Time, h

but faster than women at the conflict visit (HR, 1.20) and
slightly faster across visits (HR, 1.066). Figure 2. Production of IL-6 (A), tumor necrosis factor ␣ (TNF-␣) (B), and
IL-1␤ (C) was lower in the blister chambers at wound sites following the
marital conflict task than after the social support task. For all 3 cytokines, the
PRODUCTION OF significant time⫻ visit interactions reflect the same or higher baseline values
CHAMBER-FLUID CYTOKINES AND CELLS at the second visit (conflict) compared with the first (social support) but
lower production at 22 hours.

As expected, cytokine production in blister chamber fluid

increased over time at both GCRC admissions (Figure 2).
However, consistent with the differences between visits in
wound healing, production of IL-6, IL-1␤, and TNF-␣ in-
creased more steeply between 4 and 22 hours following the
social support interaction than after the conflict interac-
tion, ending up higher at 22 hours at the first visit for all 3
cytokines (IL-6, F2,81 = 3.55; P = .03; IL-1␤, F2,81 = 9.12;
P⬍.001; TNF-␣, F2,81 =3.56; P=.03). At the social support
visit, subjects with high-hostile behaviors had lower TNF-␣
levels than subjects with low-hostile behaviors (overall mean
[SD], 3.08 [0.11] vs 3.32 [0.07], respectively), but at the
conflict visit, subjects with high-hostile behaviors had higher
TNF-␣ levels (overall mean [SD], 3.25 [0.11] vs 3.19 [0.07],
respectively) (F1,81 =4.99; P=.03). High-hostile subjects also
had significantly fewer cells in the blister chamber fluid than
low-hostile subjects during both GCRC admissions, re-
flected in area under the curve differences across time
(F1,78 =10.5; P=.002).
The substantial increases in local cytokine produc-
tion over time (Figure 2) have been assumed to be pri-
marily a function of their local synthesis at the site by
the cells that are migrating to the chamber.22,58 In our data,
correlations between cell numbers and cytokine levels
at 22 hours after the social support interaction were r=0.29
and P⬍.01 for IL-6; r=0.08 and P =.45 for TNF-␣; and
r=0.13 for IL-1␤ and after the conflict interaction, r=0.52
and P⬍.001 for IL-6 and r =0.38 and P⬍.001 for both
TNF-␣ and IL-1␤. Consistent with other investiga-
tors,22,58 there were not reliable relationships between the
local production of cytokines at inflammatory sites and
levels in systemic circulation (data not shown); thus, lo-
cal production is the primary presumptive pathway.22,58

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A
High-Hostile Group
Low-Hostile Group
0.80
0.70
IL-6 (log10), pg/mL
0.60
0.50
0.40
0.30
GCRC Entry GCRC Exit GCRC Entry
B healing appeared to be responsive to both the short-term
1.30
TNF-α (log10), pg/mL
1.20
1.10
1.00
GCRC Entry GCRC Exit GCRC Entry
Social Support
Figure 3. Changes in plasma IL-6 (A) and tumor necrosis factor ␣ (TNF-␣)
(B) levels in couples high or low in hostile behavior. The respective cytokines
are shown at the beginning and end of each the two 24-hour social support
and conflict interaction admissions. Low-hostile participants showed roughly
the same increase in IL-6 levels over 24 hours following either a social
support or conflict interaction (65% vs 70%), while IL-6 production for
high-hostile individuals jumped from 45% following the social support task
to 113% following the conflict task. High-hostile participants had higher
TNF-␣ values before and after the conflict task than low-hostile participants.
GCRC indicates General Clinical Research Center.
PLASMA PROINFLAMMATORY
CYTOKINE LEVELS
High-hostile couples produced larger increases in
plasma IL-6 and TNF-␣ levels the morning after a con-
flict than a social support interaction (Figure 3), while
low-hostile couples showed 24-hour increases in IL-6
levels that were similar at each visit and a smaller 24-
hour increase in TNF-␣ levels at the conflict visit com-
pared with the social support visit as reflected in the
significant 3-way GCRC admission⫻time ⫻hostile be-
havior interactions for both IL-6 (F1,40 = 4.75; P = .04)
and TNF-␣ (F1,40 = 7.81; P = .008). Both groups dis-
played the expected increases in IL-6 and TNF-␣ levels
over 24 hours at each visit.59 Women had significantly
higher IL-6 levels than men (F1,40 = 5.28; P⬍.001), and
men had significantly higher TNF-␣ levels than women
(F1,40 =5.28; P= .03).
HEALTH-RELATED BEHAVIORS
Further analyses assessed the possibility that the relation-
ships between hostile behavior and cytokine levels and
wound healing might simply reflect the contribution of
health habits and/or chronic health problems. However,
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none of the health-related behaviors accounted for differ-
ences between hostile behavior groups (F ⬍1 for all).
COMMENT
Blister wounds healed more slowly following couples’ con-
flict discussions than after more supportive inter-
changes, and couples who were more hostile toward each
other during both discussions had wounds that healed more
slowly than couples whose interactions were less hostile.
The overall differences related to hostility were substan-
GCRC Exit
tial; small blister wounds in high-hostile couples healed
at only 60% of the rate of low-hostile couples. Thus, wound
stress of a conflict, as well as hostile behaviors.
Compared with low-hostile behavior couples, high-
hostile couples had relatively greater increases in circu-
lating levels of plasma IL-6 and TNF-␣ following a con-
flict discussion than a social support interaction. Indeed,
low-hostile participants produced roughly the same in-
crement in IL-6 production over 24 hours following either
a social support or conflict interaction (65% vs 70%), while
IL-6 production for high-hostile individuals jumped from
45% to 113%.
GCRC Exit These changes are important because both stressors and
Conflict depression can sensitize the inflammatory response in such
a way that they produce heightened responsiveness to
stressful events as well as antigen challenge.25,27,28,60 Fur-
thermore, more frequent or persistent stress-related changes
in plasma levels of these key cytokines have broad impli-
cations for health; elevated levels of proinflammatory cy-
tokines have been linked to a variety of age-related dis-
ease, including cardiovascular disease, osteoporosis,
arthritis, type 2 diabetes mellitus, certain cancers, and
frailty and functional decline.29 Moreover, inflammatory
activation can enhance development of depressive
symptoms.30,31 Thus, relationships characterized by hos-
tility, repeated conflicts, and heightened IL-6 levels
could have negative consequences for both physical and
mental health. Indeed, our data are consistent with the
growing epidemiological evidence that marital stress is
a risk factor for mental and physical health.
The 2 GCRC admissions allowed us to separate the
effects of the short-term stress of a marital conflict from
the long-term strains of marital dissatisfaction. Couples
were understandably apprehensive when they came for
the first GCRC admission, and their higher negative affect
on the first GCRC admission compared with the second
reflected this initial concern. Prior work with the blister-
chamber model showed that even modest levels of stress
prior to wounding were reflected in lower production of
proinflammatory cytokines at the wound site.21 Thus, the
fact that the social support interaction always occurred
at the first GCRC admission and yet wound healing and
local IL-6, TNF-␣, and IL-1␤ production were all poorer
following conflict suggests that the effects of the dis-
agreement were larger than our data suggest.
Furthermore, couples’ fights at home are more nega-
tive and last longer than those studied in the labora-
tory.37 Unhappy couples are less likely to volunteer for
marital research than those who are more satisfied with
WWW.ARCHGENPSYCHIATRY.COM
1382
their spouse.38 Accordingly, the present data are likely
to underestimate the health impact of marital strife.
Limitations of the study include the relatively small
sample of couples and the number of analyses con-
ducted on the data. Although our hypotheses were largely
supported, women did not show greater physiological re-
sponsiveness to conflict than men. Moreover, even though
the pattern for high- vs low-hostile participants was gen-
erally consistent, high-hostile individuals did produce
more TNF-␣ at the wound sites during the conflict ad-
mission than during the social support admission, while
low-hostile individuals showed a sharper increase in
plasma TNF-␣ levels during the social support admis-
sion than high-hostile individuals.
Compared with the low-hostile behavior group, high-
hostile participants had fewer positive behaviors, lower
marital satisfaction, and reported more negative affect af-
ter interacting with their spouse. If abrasive relationships
provoke larger and more frequent adverse immunologi-
cal changes, then individuals in troubled relationships could
be at greater risk for a variety of health problems over time.
Distressed families experience roughly twice as many ten-
sions per day as nondistressed families.61,62 There is also
greater spillover of conflict from one topic to another and
greater “contagion” between marital and child-related
tensions among unhappy couples than those who are
more satisfied.62 Moreover, distressed couples are more
likely to have continuing conflicts that recur in well-
established patterns at the same time on subsequent days.62
Accordingly, these data provide a window on the path-
ways through which close personal relationships may
affect physiological functioning and health. If chroni-
cally hostile or abrasive relationships produce more fre-
quent and more pronounced proinflammatory cytokine
changes, then individuals in troubled relationships could
be at greater risk over time.
Submitted for Publication: March 18, 2005; final revi-
sion received May 10, 2005; accepted May 23, 2005.
Correspondence: Janice K. Kiecolt-Glaser, PhD, De-
partment of Psychiatry, Ohio State University College
of Medicine, 1670 Upham Dr, Columbus, OH 43210
(kiecolt-glaser.1@osu.edu).
Funding/Support: This research was supported in part
by grants AG16321, DE13749, and MH18831 and Gen-
eral Clinical Research Center Grant MO1-RR-0034 from
the National Institutes of Health, Bethesda, Md, and Ohio
State University Comprehensive Cancer Center Core
Grant CA16058.
Previous Presentation: Portions of these data were pre-
sented as part of the Patricia R. Barchas Award lecture at
the annual meeting of the American Psychosomatic So-
ciety; March 3, 2005; Vancouver, British Columbia.
REFERENCES
1. House JS, Landis KR, Umberson D. Social relationships and health. Science. 1988;
241:540-545.
2. Chandra V, Szklo M, Goldberg R, Tonascia J. The impact of marital status on
survival after an acute myocardial infarction: a population-based study. Am J
Epidemiol. 1983;117:320-325.
3. Goodwin JS, Hunt WC, Key CR, Samet JM. The effect of marital status on stage,
treatment, and survival of cancer patients. JAMA. 1987;258:3125-3130.
(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 62, DEC 2005
1383
Downloaded from www.archgenpsychiatry.com at Bristol-Myers Squibb, on December 28, 2005
©2005 American Medical Association. All rights reserved.
4. Gordon HS, Rosenthal GE. Impact of marital status on outcomes in hospitalized
patients. Arch Intern Med. 1995;155:2465-2471.
5. Kiecolt-Glaser JK, Newton T. Marriage and health: His and hers. Psychol Bull.
2001;127:472-503.
6. Irwin M, Daniel M, Risch SC, Bloom E, Weiner H. Plasma cortisol and natural
killer cell activity during bereavement. Biol Psychiatry. 1988;24:173-178.
7. Schleifer S, Keller S, Camerino M, Thorton JC, Stein M. Suppression of lympho-
cyte stimulation following bereavement. JAMA. 1983;250:374-377.
8. Coyne JC, DeLongis A. Going beyond social support: the role of social relation-
ships in adaptation. J Consult Clin Psychol. 1986;54:454-460.
9. Weissman MM. Advances in psychiatric epidemiology: rates and risks for major
depression. Am J Public Health. 1987;77:445-451.
10. O’Leary KD, Christian JL, Mendell NR. A closer look at the link between marital
discord and depressive symptomatology. J Soc Clin Psychol. 1994;13:33-
41.
11. Orth-Gomer K, Wamala SP, Horsten M, Schenck-Gustafsson K, Schneiderman
N, Mittleman MA. Marital stress worsens prognosis in women with coronary heart
disease. JAMA. 2000;284:3008-3014.
12. Coyne JC, Rohrbaugh MJ, Shoham V, Sonnega JS, Nicklas JM, Cranford JA.
Prognostic importance of marital quality for survival of congestive heart failure.
Am J Cardiol. 2001;88:526-529.
13. Kimmel PL, Peterson RA, Weihs KL, Shidler N, Simmens SJ, Alleyne S, Cruz I,
Yanovski JA, Veis JH, Phillips TM. Dyadic relationship conflict, gender, and mor-
tality in urban hemodialysis patients. J Am Soc Nephrol. 2000;11:1518-1525.
14. Ewart CK, Taylor CB, Kraemer HC, Agras WS. High blood pressure and marital
discord: not being nasty matters more than being nice. Health Psychol. 1991;
10:155-163.
15. Kiecolt-Glaser JK, Malarkey WB, Chee M, Newton T, Cacioppo JT, Mao HY, Gla-
ser R. Negative behavior during marital conflict is associated with immunologi-
cal down-regulation. Psychosom Med. 1993;55:395-409.
16. Malarkey W, Kiecolt-Glaser JK, Pearl D, Glaser R. Hostile behavior during mari-
tal conflict alters pituitary and adrenal hormones. Psychosom Med. 1994;56:
41-51.
17. Kiecolt-Glaser JK, Newton T, Cacioppo JT, MacCallum RC, Glaser R, Malarkey
WB. Marital conflict and endocrine function: are men really more physiologi-
cally affected than women? J Consult Clin Psychol. 1996;64:324-332.
18. Kiecolt-Glaser JK, Glaser R, Cacioppo JT, MacCallum RC, Snydersmith M, Kim
C, Malarkey WB. Marital conflict in older adults: endocrinological and immuno-
logical correlates. Psychosom Med. 1997;59:339-349.
19. Kiecolt-Glaser JK, Marucha PT, Malarkey WB, Mercado AM, Glaser R. Slowing
of wound healing by psychological stress. Lancet. 1995;346:1194-1196.
20. Marucha PT, Kiecolt-Glaser JK, Favagehi M. Mucosal wound healing is impaired
by examination stress. Psychosom Med. 1998;60:362-365.
21. Glaser R, Kiecolt-Glaser JK, Marucha PT, MacCallum RC, Laskowski BF, Malar-
key WB. Stress-related changes in proinflammatory cytokine production in wounds.
Arch Gen Psychiatry. 1999;56:450-456.
22. Kuhns DB, DeCarlo E, Hawk DM, Gallin JI. Dynamics of the cellular and humoral
components of the inflammatory response elicited in skin blisters in humans.
J Clin Invest. 1992;89:1734-1790.
23. Kirsner RS, Eaglstein WH. The wound healing process. Dermatol Clin. 1993;11:
629-640.
24. Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications
for health. Nat Rev Immunol. 2005;5:243-251.
25. Zhou D, Kusnecov AW, Shurin MR, DePaoli M, Rabin BS. Exposure to physical
and psychological stressors elevates plasma interleukin 6: relationship to the ac-
tivation of hypothalamic-pituitary-adrenal axis. Endocrinology. 1993;133:2523-
2530.
26. Penninx BWJH, Kritchevsky SB, Yaffe K, Newman AB, Simonsick EM, Rubin S,
Ferrucci L, Harris T, Pahor M. Inflammatory markers and depressed mood in
older persons: results from the health, aging, and body composition study. Biol
Psychiatry. 2003;54:566-572.
27. Glaser R, Robles T, Sheridan J, Malarkey WB, Kiecolt-Glaser JK. Mild depres-
sive symptoms are associated with amplified and prolonged inflammatory re-
sponses following influenza vaccination in older adults. Arch Gen Psychiatry. 2003;
60:1009-1014.
28. Maes M, Ombelet W, De Jongh R, Kenis G, Bosmans E. The inflammatory re-
sponse following delivery is amplified in women who previously suffered from
major depression, suggesting that major depression is accompanied by a sen-
sitization of the inflammatory response system. J Affect Disord. 2001;63:85-
92.
29. Harris T, Ferrucci L, Tracy R, Corti MC, Wacholder S, Ettinger WH Jr, Heimovitz
H, Cohen HJ, Wallace R. Associations of elevated interleukin-6 and C-reactive
protein levels with mortality in the elderly. Am J Med. 1999;106:506-512.
30. Raison CL, Miller AH. Depression in cancer: new developments regarding diag-
nosis and treatment. Biol Psychiatry. 2003;54:283-294.
WWW.ARCHGENPSYCHIATRY.COM
31. Irwin M. Psychoneuroimmunology of depression: clinical implications. Brain Be-
hav Immun. 2002;16:1-16.
32. Pasch LA, Bradbury TN. Social support, conflict, and the development of marital
dysfunction. J Consult Clin Psychol. 1998;66:219-230.
33. Veroff J, Sutherland L, Chadiha L, Ortega RM. Newlyweds tell their stories: a nar-
rative method for assessing marital experiences. J Soc Pers Relat. 1993;10:
437-457.
34. Knox D. Marriage Happiness. Champaign, Ill: Research Press; 1971.
35. Heyman RE. Rapid Marital Interaction Coding System (RMICS). In: Kerig PK, Bau-
com DH, eds. Couple Observational Coding Systems. Nahwah, NJ: Lawrence
Erlbaum Associates; 2004:67-94.
36. Crowell JA, Treboux D, Gao Y, Fyffe C, Pan H, Waters E. Assessing secure base
behavior in adulthood: development of a measure, links to adult attachment rep-
resentations, and relations to couples’ communication and reports of relationships.
Dev Psychol. 2002;38:679-693.
37. Margolin G, Burman B, John RS. Home observations of married couples reen-
acting naturalistic conflicts. Behav Assess. 1989;11:101-118.
38. Bradbury TN, Karney BR. Longitudinal study of marital interaction and dysfunc-
tion: review and analysis. Clin Psychol Rev. 1993;13:15-27.
39. Jacob T, Krahn G. The classification of behavioral observation codes in studies
of family interaction. J Marriage Fam. 1987;49:677-687.
40. Heyman RE, Weiss RL, Eddy JML. Marital Interaction Coding System: revision
and empirical evaluation. Behav Res Ther. 1995;33:737-746.
41. Watson D, Clark LA, Tellegen A. Development and validation of brief measures
of positive and negative affect: the PANAS scales. J Pers Soc Psychol. 1988;
54:1063-1070.
42. Locke HJ, Wallace KM. Short marital adjustment and prediction tests: their re-
liability and validity. Marriage Fam Living. 1959;21:251-255.
43. Kiecolt-Glaser JK, Glaser R. Psychological influences on immunity: implications
for AIDS. Am Psychol. 1988;43:892-898.
44. Baecke JAH, Burema J, Frijters JER. A short questionnaire for the measurement
of habitual physical activity in epidemiological studies. Am J Clin Nutr. 1982;
36:936-942.
45. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. Pittsburgh Sleep Qual-
ity Index: a new instrument for psychiatric practice and research. Psychiatry Res.
1989;28:193-213.
46. Fillenbaum GG, Smyer MA. The development, validity, and reliability of the OARS
Multidimensional Functional Assessment Questionnaire. J Gerontol. 1981;
36:428-434.
47. Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Gla-
ser R. Chronic stress and age-related increases in the proinflammatory cytokine
IL-6. Proc Natl Acad Sci U S A. 2003;100:9090-9095.
48. Kuhns DB, Gallin JI. Increased cell-associated IL-8 in human exudative and A23187-
treated peripheral blood neutrophils. J Immunol. 1995;154:6556-6562.
49. Zimmerli W, Gallin JI. Monocytes accumulate on Rebuck skin window cover-
slips but not in skin chamber fluid: a comparative evaluation of two in vivo mi-
gration models. J Immunol Methods. 1987;96:11-17.
50. Svedman P, Svedman C, Njalsson T. Epithelialization and blood flow in suction
blister wounds on healthy volunteers. J Invest Surg. 1991;4:175-189.
51. Smit HA, Pinnagoda J, Tupker RA, Burema J, Coenraads PJ, Nater JP. Variabil-
ity in transepidermal water loss of the skin: evaluation of a method to assess
susceptibility to contact dermatitis in epidemiological studies. Int Arch Occup
Environ Health. 1990;62:509-512.
52. Pinnagoda J, Tupker RA, Agner T, Serup J. Guidelines for transepidermal water
loss (TEWL) measurement. Contact Dermatitis. 1990;22:164-178.
53. Lindahl KM, Clements M, Markman H. Predicting marital and parent functioning
in dyads and triads: a longitudinal investigation of marital processes. J Fam Psychol.
1997;11:139-151.
54. Hosmer DW, Lemeshow S. Applied Survival Analysis. New York, NY: John Wiley
& Sons; 1999.
55. Lin DY, Wei LJ. The robust inference for the Cox proportional hazards model.
J Am Stat Assoc. 1989;84:1074-1078.
56. Watson D. Intraindividual and interindividual analyses of positive and negative
affect: their relation to health complaints, perceived stress, and daily activities.
J Pers Soc Psychol. 1988;54:1020-1030.
57. Lutgendorf SK, Garand L, Buckwalter KC, Reimer TT, Hong S, Lubaroff DM.
Life stress, mood disturbance, and elevated interleukin-6 in healthy older women.
J Gerontol A Biol Sci Med Sci. 1999;54:M434-M439.
58. Yee J, Christou NV. The local role of tumor necrosis factor alpha in the modu-
lation of neutrophil function at sites of inflammation. Arch Surg. 1994;129:
1249-1255.
59. Gudmundsson A, Ershler WB, Goodman B, Lent SJ, Barczi S, Carnes M. Serum
concentrations of interleukin-6 are increased when sampled through an indwell-
ing venous catheter. Clin Chem. 1997;43:2199-2201.
60. Johnson JD, O’Connor KA, Deak T, Stark M, Watkins LR, Maier SF. Prior stressor
exposure sensitizes LPS-induced cytokine production. Brain Behav Immun. 2002;
16:461-476.
61. Christensen A, Margolin G. Conflict and alliance in distressed and nondis-
tressed families. In: Hinde RA, Stevenson-Hinde J, eds. Relationships Within Fami-
lies: Mutual Influences. Oxford, England: Clarendon; 1988:263-282.
62. Margolin G, Christensen A, John RS. The continuance and spillover of everyday
tensions in distressed and nondistressed families. J Fam Psychol. 1996;10:
304-321.

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